The The PROPROspective spective MMulticenter ulticenter IImaging maging SStudy for tudy for EEvaluation of valuation of Chest Pain (PROMISE) Trial: Economic OutcomesChest Pain (PROMISE) Trial: Economic Outcomes

March 15, 2015March 15, 2015

Daniel B. Mark, MD, MPHDaniel B. Mark, MD, MPHProfessor of MedicineProfessor of Medicine

Vice Chief for Academic Affairs, Cardiology DivisionVice Chief for Academic Affairs, Cardiology DivisionDuke University Medical CenterDuke University Medical CenterDirector, Outcomes ResearchDirector, Outcomes Research

Duke Clinical Research InstituteDuke Clinical Research Institute

Financial DisclosuresFinancial DisclosuresConsultingConsultingMilestoneMilestoneMedtronicMedtronicCardioDxCardioDxSt Jude MedicalSt Jude Medical

Research GrantsResearch GrantsNIHNIHEli Lilly & CompanyEli Lilly & CompanyAstraZenecaAstraZenecaGileadGileadAGA MedicalAGA MedicalBristol Myers SquibbBristol Myers Squibb

Co-Investigators/Econ TeamCo-Investigators/Econ TeamKevin AnstromKevin AnstromPatricia CowperPatricia Cowper

Linda Davidson RayLinda Davidson RayUdo HoffmannUdo HoffmannManesh PatelManesh Patel

Lawton CooperLawton CooperKerry LeeKerry Lee

Pamela DouglasPamela DouglasJeff FederspielJeff FederspielMelanie DanielsMelanie Daniels

PROMISE Trial Background:PROMISE Trial Background:Moving From Controversy to EvidenceMoving From Controversy to Evidence

• Noninvasive ability to directly visualize the coronary arteries of Noninvasive ability to directly visualize the coronary arteries of patients with chest pain has long been on Cardiology’s Wish List patients with chest pain has long been on Cardiology’s Wish List

• As coronary CT angiography evolved into a test that might actually As coronary CT angiography evolved into a test that might actually be able to fulfill this wish, controversy broke out be able to fulfill this wish, controversy broke out

• The PRO side: CTA would allow precision care - only the patients The PRO side: CTA would allow precision care - only the patients who needed revascularization would actually go to cath and the rest who needed revascularization would actually go to cath and the rest would avoid it – would avoid it – invasive testing, invasive testing, unneeded revascularization, unneeded revascularization, false positives, false positives, $$$$

• The CON side: CTA would: The CON side: CTA would: non-invasive and invasive testing to non-invasive and invasive testing to clarify ambiguous findings, clarify ambiguous findings, radiation exposure, radiation exposure, $$ $$

PROMISE: Design OverviewPROMISE: Design Overview

•New or worsening chest pain or symptoms w/out known CADNew or worsening chest pain or symptoms w/out known CAD•Low to intermediate riskLow to intermediate risk•Planned noninvasive testing for diagnosisPlanned noninvasive testing for diagnosis

10,003 patients with symptoms of CAD10,003 patients with symptoms of CAD

1:1 Randomization1:1 RandomizationStratified by site and intended Stratified by site and intended

functional testfunctional test

Usual Care ArmUsual Care ArmPre-selected Functional TestingPre-selected Functional Testing

Intervention ArmIntervention ArmAnatomic Testing 64-slice CTAAnatomic Testing 64-slice CTA

Median study follow-up 25.2 monthsMedian study follow-up 25.2 months

11° endpoint: composite of death, MI, UA hosp, or major procedural complication° endpoint: composite of death, MI, UA hosp, or major procedural complication2° aims incl.: cost and cost effectiveness2° aims incl.: cost and cost effectiveness

193 sites193 sites(US, CA)(US, CA)

PROMISE Trial:PROMISE Trial:CTA Patient Outcomes Not Superior to Functional TestingCTA Patient Outcomes Not Superior to Functional Testing

““Strategy of initial CTA, as compared with Strategy of initial CTA, as compared with functional testing, did not improve clinical functional testing, did not improve clinical outcomes over a median follow-up of 2 years.”outcomes over a median follow-up of 2 years.”

Douglas PS et alDouglas PS et alNEJM 2015NEJM 2015

PROMISE Primary Endpoint Results:PROMISE Primary Endpoint Results:Death, MI, Unstable Angina, Major Procedural ComplicationsDeath, MI, Unstable Angina, Major Procedural Complications

Douglas PS et alDouglas PS et alNEJM 2015NEJM 2015

PROMISE Economic Substudy:PROMISE Economic Substudy:Primary ObjectivesPrimary Objectives

• Measure and compare cumulative total costs as Measure and compare cumulative total costs as randomizedrandomized

• If CTA outcomes superior, estimate cost effectiveness If CTA outcomes superior, estimate cost effectiveness of anatomic strategyof anatomic strategy

PROMISE Economic Substudy:PROMISE Economic Substudy:Calculation of Medical CostsCalculation of Medical Costs

• 96% (9649) of PROMISE cohort in Economic Substudy96% (9649) of PROMISE cohort in Economic Substudy

• Initial diagnostic test technical feesInitial diagnostic test technical fees- Bottom up estimate (resource-based cost accounting methods) from Bottom up estimate (resource-based cost accounting methods) from

large proprietary registry (Premier Research Database)large proprietary registry (Premier Research Database)

• Hospital-based facility costs Hospital-based facility costs

- UB 04 bill forms provide hospital charges by departmentUB 04 bill forms provide hospital charges by department- Department-specific ratios of costs to charges (RCCs) used to convert Department-specific ratios of costs to charges (RCCs) used to convert

charges to estimates of costcharges to estimates of cost

• MD professional fees for testing and hospital servicesMD professional fees for testing and hospital services- Medicare Fee ScheduleMedicare Fee Schedule

PROMISE Economic Substudy:PROMISE Economic Substudy:Analysis MethodsAnalysis Methods

• Comparisons by intention to treat principleComparisons by intention to treat principle

• Costs to 3 years estimated, accounting for censoring using Costs to 3 years estimated, accounting for censoring using inverse probability weighting methodsinverse probability weighting methods

• Bootstrapped confidence intervals: 1000 replications (500 Bootstrapped confidence intervals: 1000 replications (500 in subgroup analyses), 95% confidence intervalsin subgroup analyses), 95% confidence intervals

PROMISE Economic Substudy:PROMISE Economic Substudy:Baseline CharacteristicsBaseline Characteristics

FunctionalFunctionalAnatomicAnatomic(N=4,818)(N=4,818)(N=4,831)(N=4,831)

Demographics Demographics      Age, meanAge, mean 60.9 ± 8.360.9 ± 8.3 60.7 ± 8.360.7 ± 8.3FemaleFemale 54%54% 52%52%Cardiac risk factors Cardiac risk factors      BMI, meanBMI, mean 30.6 ± 6.230.6 ± 6.2 30.6 ± 6.230.6 ± 6.2HypertensionHypertension 66%66% 66%66%DiabetesDiabetes 22%22% 22%22%DyslipidemiaDyslipidemia 68%68% 67%67%Family history premature CADFamily history premature CAD 32%32% 33%33%Current or past smokingCurrent or past smoking 51%51% 51%51%Primary symptom chest pain or DOEPrimary symptom chest pain or DOE   88%88%   88%88%Typical or atypical anginaTypical or atypical angina 89%89% 89%89%Pretest probability of CADPretest probability of CAD 53%53% 54%54%

PROMISE Economic Substudy:PROMISE Economic Substudy:Estimation of Initial Diagnostic Testing CostsEstimation of Initial Diagnostic Testing Costs

Dx TestDx Test

CTACTA

Echo w/ exercise stressEcho w/ exercise stressEcho w/ pharmacologic stressEcho w/ pharmacologic stress

ECG-only StressECG-only Stress

Nuclear w/ exercise stressNuclear w/ exercise stressNuclear w/ pharmacologic stressNuclear w/ pharmacologic stress

Mean Cost*Mean Cost*

$285$285

$428$428$415$415

$137$137

$829$829$1015$1015

*based on costs in Premier database*based on costs in Premier database**based on Medicare Fee Schedule **based on Medicare Fee Schedule

MD Fees**MD Fees**

$119$119

$86$86$86$86

$37$37

$117$117$117$117

TotalTotal

$404$404

$514$514$501$501

$174$174

$946$946$1132$1132

PROMISE Economic Substudy:PROMISE Economic Substudy:Cumulative Total Costs by ITT and Mean Cost Difference (95%CI)Cumulative Total Costs by ITT and Mean Cost Difference (95%CI)

$279$279 $358$358 $388$388

$694$694

Cumulative CostCumulative Cost Difference in CostDifference in Cost(Anatomic – Functional)(Anatomic – Functional)

PROMISE Secondary Endpoints:PROMISE Secondary Endpoints:90-Day Catheterization and Revascularization Rates90-Day Catheterization and Revascularization Rates

Invasive cathInvasive cath

RevascularizationRevascularization

No CAD on cathNo CAD on cath

CTACTA(n=4996)(n=4996)

609 (12.2%)609 (12.2%)

311 (6.2%)311 (6.2%)(51% of cath patients)(51% of cath patients)

170 (3.4%)170 (3.4%)

(28% of cath patients)(28% of cath patients)

FunctionalFunctional(n=5007)(n=5007)

406 (8.1%)406 (8.1%)

158 (3.2%)158 (3.2%)(39% of cath patients)(39% of cath patients)

213 (4.3%)213 (4.3%)

(52% of cath patients)(52% of cath patients)

PROMISE Economic Substudy:PROMISE Economic Substudy:Cost Differences by Categories 0-3 and 4-12 MonthsCost Differences by Categories 0-3 and 4-12 Months

-$378-$378 $68$68 $357$357 $203$203 $17$17 $12$12 $279$279 -$17-$17 $49$49 $43$43 -$10-$10 $8$8 $8$8 $81$81

PROMISE Economic Substudy:PROMISE Economic Substudy:Cost Differences by Categories Years 2 and 3Cost Differences by Categories Years 2 and 3

$35$35 -$12-$12 -$69-$69 $7$7 $15$15 $53$53 $29$29$10$10 $20$20 -$35-$35 -$97-$97 $311$311 $97$97 $306$306

PROMISE Economic Substudy:PROMISE Economic Substudy:2-Year Cost Difference Thresholds From Bootstrap Analysis2-Year Cost Difference Thresholds From Bootstrap Analysis

Cumulative Cumulative distribution of distribution of mean cost mean cost difference difference [CTA-FXN] [CTA-FXN] from 1000 from 1000 bootstrap bootstrap replications replications out to 24 out to 24 monthsmonths

Cost difference: Cost difference: << $500 – 62% of samples $500 – 62% of samples<< $750 – 81% of samples $750 – 81% of samples<< $1000 – 93% of samples $1000 – 93% of samples

PROMISE Economic Substudy: PROMISE Economic Substudy: Pre-Randomization MD Choice of Functional Test SubgroupsPre-Randomization MD Choice of Functional Test Subgroups

Overall (N= 9,649)

ECG-Only (N= 858)

Echo (N= 2,204)

Nuclear (N= 6,587)

Mean Cost Difference Mean Cost Difference

Months 0-3Months 0-3 Months 0-36Months 0-36

PROMISE Economic Substudy:PROMISE Economic Substudy:CaveatsCaveats

• Costs of initial testing from external data sourceCosts of initial testing from external data source

• Significant deviations by centers from testing costs Significant deviations by centers from testing costs used in this analysis might alter relative cost used in this analysis might alter relative cost positions of the two strategiespositions of the two strategies

• Outpatient medications not countedOutpatient medications not counted

• QOL and employment status still being analyzedQOL and employment status still being analyzed

PROMISE Economic Substudy:PROMISE Economic Substudy:SummarySummary

• In stable patients with new chest pain, CTA strategy improved efficiency of use of In stable patients with new chest pain, CTA strategy improved efficiency of use of invasive cath (fewer normal caths, higher proportion of caths also getting revasc) invasive cath (fewer normal caths, higher proportion of caths also getting revasc)

• But despite lower testing costs for CTA compared with stress echo (~$100 less) and But despite lower testing costs for CTA compared with stress echo (~$100 less) and stress nuclear (~$630 less), net effect was to drive a small (<$500), statistically non-stress nuclear (~$630 less), net effect was to drive a small (<$500), statistically non-significant increase in costsignificant increase in cost

• After 90 days, very little test strategy-related differences in costs out to 3 yearsAfter 90 days, very little test strategy-related differences in costs out to 3 years

• Coronary CTA may not be the “holy grail” of diagnostic testing once hoped for, but its Coronary CTA may not be the “holy grail” of diagnostic testing once hoped for, but its more liberal use following PROMISE standards will improve some aspects of care more liberal use following PROMISE standards will improve some aspects of care without causing a major new economic burden on the health care systemwithout causing a major new economic burden on the health care system